US20060135943A1 - Method and apparatus for treating vulnerable plaque - Google Patents

Abstract

An apparatus and method to treat vulnerable plaque. In one embodiment, the apparatus has an elongated catheter body adapted for insertion in a body lumen, with a drug delivery device attached near a distal portion of the elongated body. The drug delivery device is configured to deliver a biologically active agent to stabilize a vulnerable plaque.

Description

• This application is a divisional application of co-pending U.S. patent application Ser. No. 10/262,151, filed Sep. 30, 2002.
FIELD OF THE INVENTION
• The invention, in one embodiment, relates generally to the treatment of coronary disease, and more particularly, in one embodiment, to the stabilization of vulnerable plaque.
BACKGROUND OF THE INVENTION
• Coronary heart disease is generally thought to be caused by the narrowing of coronary arteries by atherosclerosis, the buildup of fatty deposits in the lining of the arteries. The process that may lead to atherosclerosis begins with the accumulation of excess fats and cholesterol in the blood. These substances infiltrate the lining of arteries, gradually increasing in size to form deposits commonly referred to as plaque or atherosclerotic occlusions. Plaques narrow the arterial lumen and impede blood flow. Blood cells may collect around the plaque, eventually creating a blood clot that may block the artery completely.
• The phenomenon of “vulnerable plaque” has created new challenges in recent years for the treatment of heart disease. Unlike occlusive plaques that impede blood flow, vulnerable plaque develops within the arterial walls, but it often does so without the characteristic substantial narrowing of the arterial lumen which produces symptoms. As such, conventional methods for detecting heart disease, such as an angiogram, may not detect vulnerable plaque growth into the arterial wall. After death, an autopsy can reveal the plaque congested in arterial wall that could not have been seen otherwise with currently available medical technology.
• The intrinsic histological features that may characterize a vulnerable plaque include increased lipid content, increased macrophage, foam cell and T lymphocyte content, and reduced collagen and smooth muscle cell (SMC) content. This fibroatheroma type of vulnerable plaque is often referred to as “soft,” having a large lipid pool of lipoproteins surrounded by a fibrous cap. The fibrous cap contains mostly collagen, whose reduced concentration combined with macrophage derived enzyme degradations can cause the fibrous cap of these lesions to rupture under unpredictable circumstances. When ruptured, the lipid core contents, thought to include tissue factor, contact the arterial bloodstream, causing a blood clot to form that can completely block the artery resulting in an acute coronary syndrome (ACS) event. This type of atherosclerosis is coined “vulnerable” because of unpredictable tendency of the plaque to rupture. It is thought that hemodynamic and cardiac forces, which yield circumferential stress, shear stress, and flexion stress, may cause disruption of a fibroatheroma type of vulnerable plaque. These forces may rise as the result of simple movements, such as getting out of bed in the morning, in addition to in vivo forces related to blood flow and the beating of the heart. It is thought that plaque vulnerability in fibroatheroma types is determined primarily by factors which include: (1) size and consistency of the lipid core; (2) thickness of the fibrous cap covering the lipid core; and (3) inflammation and repair within the fibrous cap.
• FIG. 1A illustrates a partial cross-section of an artery having a narrowed arterial lumen caused by the presence of occlusive atherosclerosis. Plaque accumulates to impede and reduce blood flow through the arterial lumen and thus often causes symptoms (e.g., angina pectoris). The arrows indicate the direction of blood flow through the arterial lumen.FIG. 1B illustrates an occlusive atherosclerosis within an arterial lumen resulting in significant reduction in lumen patency. This type of atherosclerosis can easily be detected through current diagnostic methods such as an angiogram.FIG. 1B also illustrates, downstream from the occlusive atherosclerosis, a fibroatheroma type of vulnerable plaque. The vulnerable plaque, with a lipid core, develops mostly within the arterial wall with minimal occlusive effects such that it is not easily detected by current diagnostic methods. This is partially due to a phenomenon known as “positive remodeling,” which allows the vessel to respond to the presence of disease. The fibroatheroma vulnerable plaque has grown into the positively remodeled arterial wall so that vessel occlusion has not been manifested. A fibrous cap surrounds the vulnerable plaque.
• FIGS. 2A-2C illustrate a cross-sectional view of the accumulation of vulnerable plaque in the arterial wall.FIG. 2A illustrates an arterial wall that is not affected by atherosclerosis. The normal arterial wall consists of an intima layer, a media layer, and an adventitia layer. The intima is in direct contact with the blood flow within the arterial lumen. The intima consists mainly of a monolayer of endothelial cells. The media consists mostly of smooth muscle cells and extracellular matrix proteins. The outermost layer of the arterial wall, the adventitia, is primarily collagenous and contains nerves, blood vessels, and lymph vessels.FIG. 2B illustrates the large presence of a fibroatheroma type vulnerable plaque surrounded by a fibrous cap within the arterial wall. The vulnerable plaque consists mainly of a large lipid core. The fibrous cap layer shields the lumen of the artery from the thrombogenic components in the core.FIG. 2C illustrates an occlusive thrombosis event resulting from the rupturing of the fibrous cap. Thrombogenic components in the vulnerable plaque contact luminal blood and cause the thrombotic event.
• Autopsy studies and other evidence strongly suggest that the presence of a current acute coronary syndrome (ACS) event and/or existing thrombus at certain plaque sites may correlate to predicting a future ACS event in a given patient. The latter indicates the likelihood of a prior thrombotic event (e.g., fibroatheroma rupture) after which the plaque was able to heal itself, or complete occlusion of the vessel was somehow prevented. Autopsy studies also indicate that it is reasonable to expect that at least one vulnerable plaque could exist in the majority of catheterization laboratory patients being treated for arterial blockage from visible, occlusive atherosclerosis. Many of the patients at highest risk, therefore, for future ACS events may already be receiving interventional treatment, even though current methods to diagnose occlusive plaques (i.e., non-vulnerable type plaque) are not effective for enabling therapy for vulnerable plaque. Furthermore, treating both the occlusive plaques and the vulnerable plaque in one procedure might be beneficial and desirable compared to separate treatments. This would provide a greater convenience to the patient and for the physician.
SUMMARY OF THE INVENTION
• An apparatus and method to treat vulnerable plaque are described. In one embodiment, the apparatus has a an elongated catheter body adapted for insertion in a body lumen, with a drug delivery device attached near a distal portion of the elongated body. The drug delivery device is configured to deliver a biologically active agent to stabilize a vulnerable plaque.
BRIEF DESCRIPTION OF THE DRAWINGS
• The present invention is illustrated by way of example, and not limitation, in the figures of the accompanying drawings in which:
• FIG. 1A illustrates a partial cross-section of an arterial lumen having occlusive plaque.
• FIG. 1B illustrates a partial cross-section of an arterial lumen having occlusive plaque and vulnerable plaque.
• FIGS. 2A-2C illustrate the vessel morphology and the rupturing of a vulnerable plaque.
• FIGS. 3A-3B illustrate the stabilization a vulnerable plaque by reducing the size of the lipid core and strengthening and increasing the thickness of the fibrous cap.
• FIG. 4 illustrates one embodiment of using a drug delivery stent to treat a vulnerable plaque downstream from an occlusive plaque.
• FIGS. 5A-5C illustrate an alternative embodiment of using a drug delivery stent to treat a vulnerable plaque downstream from an occlusive plaque.
• FIG. 6 illustrates one embodiment of microparticles released towards a vulnerable plaque.
• FIG. 7 illustrates one embodiment of a stent graft used to treat a vulnerable plaque.
• FIGS. 8A-8B illustrate cross-sectional views of a stent graft.
• FIGS. 9A-9D illustrate various embodiments of using a needle catheter to treat a vulnerable plaque.
• FIGS. 10A-10B illustrate one embodiment of a needle catheter.
• FIGS. 11A-11D illustrate various methods for treating vulnerable plaque.
• FIG. 12 illustrates one embodiment of inducing therapeutic angiogenesis growth near a vulnerable plaque.
• FIGS. 13A-13B illustrate cross-sectional views of one embodiment of a drug eluting stent that can be used to strengthen and to increase the thickness of the fibrous cap of the vulnerable plaque in a controlled manner.
DETAILED DESCRIPTION
• In the following description, numerous specific details are set forth such as examples of specific, components, processes, etc. in order to provide a thorough understanding of various embodiment of the present invention. It will be apparent, however, to one skilled in the art that these specific details need not be employed to practice various embodiments of the present invention. In other instances, well known components or methods have not been described in detail in order to avoid unnecessarily obscuring various embodiments of the present invention. The term “coupled” as used herein means connected directly to or indirectly connected through one or more intervening components, structures or elements. The terms “drugs,” “bioactive agents,” and “therapeutic agents” are used interchangeably to refer to agents (e.g., chemical substances) to treat, in one embodiment, coronary artery and related diseases including for example, atherosclerotic occlusions and vulnerable plaque.
• Apparatuses and their methods of use to treat vulnerable plaque are described. In one embodiment, the vulnerable plaque or the region of the artery containing the vulnerable plaque may be treated alone or in combination with treating occlusive atherosclerosis. The benefit is that any vulnerable, but not yet occlusive plaques would be treated without having to place a therapeutic implant (e.g., a stent) at the vulnerable plaque region. The only implant placed would be that already being used to scaffold and treat the existing occlusive plaque. In the following description, the stabilization of vulnerable plaque is described with respect to treatment within the artery. The coronary artery is just one region in the body where vulnerable plaque may form. As such, it can be appreciated that the stabilization of vulnerable plaque may be achieved in any vessel of the body where vulnerable plaque may exist.
• FIGS. 3A-3B illustrate a cross-sectional view of the stabilization of vulnerable plaque.FIG. 3A shows a largevulnerable plaque310 havinglipid core315 separated fromarterial lumen330 by thinfibrous cap320. Thin fibrous caps and reduced collagen content or degraded collagen in the fibrous caps increase a plaque's vulnerability to rupture. As illustrated inFIG. 3B,vulnerable plaque310 has been stabilized by thickening and/or strengtheningfibrous cap320 that separateslipid core315 fromarterial lumen330. This reduces the likelihood offibrous cap320 rupturing. Additionally,lipid core315 redistribution has occurred in combination with strengtheningfibrous cap320.Vulnerable plaque310 may also be treated by inducing collateral artery or vessel growth near the vulnerable plaque region such that, in the event of fibrous cap rupture or occlusive thrombosis, an alternative blood path exists to bypass the ruptured region (not shown).
• Drug Eluting Stents
• In one embodiment, a drug eluting stent may be implanted at the region of vessel occlusion that may be upstream from a vulnerable plaque region. As discussed above, autopsy studies have shown that vulnerable plaque regions commonly exist in the vicinity of occlusive plaques. A medical device, such as a drug eluting stent, may be used to treat the occlusive atherosclerosis (i.e., non-vulnerable plaque) while releasing a drug or biologically active agent to treat a vulnerable plaque region distal or downstream to the occlusive plaque. The drug may be released slowly over time, and may include for example, anti-inflammatory or anti-oxidizing agents. Biologically active agents may also be released include cells, proteins, peptides, and related entities.
• The eluting stent may have the vulnerable plaque treating drug or agent dispersed on the surface of the stent, or co-dissolved in a matrix solution to be dispersed on the stent. Other methods to coat the stent with a vulnerable plaque treating drug include dip coating, spin coating, spray coating, or other coating methods commonly practiced in the art.
• In one embodiment, therapeutic or biologically active agents may be released to induce therapeutic angiogenesis, which refers to the processes of causing or inducing angiogenesis and arteriogenesis, either downstream, or away from the vulnerable plaque. Arteriogenesis is the enlargement of pre-existing collateral vessels. Collateral vessels allow blood to flow from a well-perfused region of the vessel into an ischemic region (from above an occlusion to downstream from the occlusion). Angiogenesis is the promotion or causation of the formation of new blood vessels downstream from the ischemic region. Having more blood vessels (e.g., capillaries) below the occlusion may provide for less pressure drop to perfuse areas with severe narrowing caused by a thrombus. In the event that an occlusive thrombus occurs in a vulnerable plaque, the myocardium perfused by the affected artery is salvaged. Representative therapeutic or biologically active agents include, but are not limited to, proteins such as vascular endothelial growth factor (VEGF) in any of its multiple isoforms, fibroblast growth factors, monocyte chemoatractant protein 1 (MCP-1), transforming growth factor alpha (TGF-alpha), transforming growth factor beta (TGF-beta) in any of its multiple isoforms, DEL-1, insulin like growth factors (IGF), placental growth factor (PLGF), hepatocyte growth factor (HGF), prostaglandin E1 (PG-E1), prostaglandin E2 (PG-E2), tumor necrosis factor alpha (TBF-alpha), granulocyte stimulating growth factor (G-CSF), granulocyte macrophage colony-stimulating growth factor (GM-CSF), angiogenin, follistatin, and proliferin, genes encoding these proteins, cells transfected with these genes, pro-angiogenic peptides such as PR39 and PR11, and pro-angiogenic small molecules such as nicotine.
• In another embodiment, therapeutic or biologically active agents to treat the vulnerable plaque may be delivered through the bloodstream or vessel wall. These therapeutic or biologically active agents include, but are not limited to, lipid lowering agents, antioxidants, extracellular matrix synthesis promoters, inhibitors of plaque inflammation and extracellular degradation, estradiol drug classes and its derivatives.
• Prospective studies of high-risk patients in whom complex plaques were found have indicated that many of the ACS events can happen within six months to one year after a patient has an occlusive atherosclerosis lesion treated. In other words, there is a clinical reason to believe that it would be efficacious to try and actively treat lesions in those patients for a three to six-month period of time after treatment of occlusive atherosclerosis to prevent a recurrent ACS event. Examples of devices to treat vulnerable plaque regions include drug eluting stents, and drug loaded bioerodable and bioadhesive microparticles.
• In one embodiment, the polymer may be coated on a stent using dip coating, spin coating, spray coating or other coating methods known in the art. The drug can alternatively be encapsulated in microparticles or nanoparticles and dispersed in a stent coating. A diffusion limiting top-coat may optionally be applied to the above coatings. The active agents may optionally be loaded on a stent together either by adding them together to the solution of the matrix polymer before coating, or by coating different layers, each containing a different agent or combination of agents. The drug eluting stent can alternatively have an active agent or a combination of agents dispersed in a bioerodable stent forming polymer.
• Vulnerable plaque regions may also be treated independent of treating occlusive lesions near the vulnerable plaque regions. In another embodiment, a vulnerable plaque treatment drug or biologically active agent may be injected through or around the fibrous cap of a vulnerable plaque. Alternatively, in the event of a thrombotic event, a drug may be injected to prevent complete occlusion of the vessel. In one embodiment, a needle catheter may be used to inject the drug. The needle catheter may be modified to accommodate the following targets around the vulnerable plaque: fibrous cap, proteoglycan-rich surface layer, subintimal lipid core, proximal or distal regions of the plaque, media containing smooth muscle cells around the lipid core, and peri-adventitial space. In another embodiment, the needle catheter may include a sensing capability to determine penetration depth of the needle. Furthermore, the needle catheter may be configured to adopt balloons of various sizes to control the angle of needle penetration. Moreover, the use of balloons would enable accurate penetration of the needle at the desired target.
• In another embodiment, a drug eluting stent may be used to strengthen or increase the thickness of the fibrous cap of the vulnerable plaque in a controlled manner. Increasing the thickness of the fibrous cap may redistribute and lower the stresses in the fibrous cap. This may stabilize the plaque and prevent it from rupturing.
• Referring toFIG. 4, adrug delivery stent450 to treat a vulnerable plaque region is illustrated.Stent450 is disposed in anarterial lumen430 to treat bothocclusive plaque460 andvulnerable plaque410 located downstream fromocclusive plaque460. As illustrated,stent450 releases a drug (indicated by arrows470) to treat thevulnerable plaque410. As discussed above, vulnerable plaque regions commonly exist near occlusive plaque, and treating both might be advantageous over separate procedures.Occlusive plaque460 has grown to cause a narrowing of thearterial lumen430.Stent450 is shown in a state before expansion to enlarge the diameter of thearterial lumen430. A dilation balloon (not shown) may be used to expandstent450, orstent450 may be made of a material that self-expands (e.g., Nitinol) so that a dilation balloon is not needed.
• As illustrated inFIG. 4,vulnerable plaque410 is located downstream of theocclusive plaque460 but does not show any vessel occlusion.Vulnerable plaque410 hassoft lipid core415 withfibrous cap420 separatingvulnerable plaque410 fromarterial lumen430. As indicated byarrows470,stent450 releases a drug or biologically active agent through the bloodstream ofarterial lumen430 to treatvulnerable plaque410. In one embodiment, lipid lowering agents may be released. Lowering of serum LDL cholesterol may lead to a reduction in the amount of cholesterol enteringvulnerable plaque410, and increases high density lipoprotein (HDL) cholesterol which may contribute to active LDL removal from thevessel wall425. Animal studies have shown that removal of lipid increases the relative collagen content offibrous cap420 and could increase the production of collagen, favoring vulnerable plaque stabilization. Lipid lowering animal studies suggest this also treatsvulnerable plaque410 by reducing local inflammation and the expression and activity of matrix-degrading enzymes, favoring collagen accumulation infibrous cap420, making it more resistant to rupture. Lipid lowering agents may also change the composition oflipid core415 to promote plaque stabilization. It is thought that the lipid lowering agents may convert the high concentration of cholesterol esters to insoluble cholesterol monohydrate crystals, resulting in a morestiff lipid core415 that is more resistant to plaque rupture. Lipid lowering agents include, but are not limited to hydroxy-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, niacin, bile acid resins, and fibrates.
• Examples of doses of agents which may be used with embodiments of the invention, such as a drug delivery stent (i.e., the stent having been loaded with a drug which is eluted/released over time or a needle catheter) are described herein. The particular effective dose may be modified based on therapeutic results, and the following exemplary doses are acceptable initial levels which may be modified based on therapeutic results.
• In an alternative embodiment, antioxidants may be released fromstent450. The oxidation of LDL cholesterol appears to have negative impact upon vessel processes during atherogenesis. Oxidized LDL binds to cell receptors on macrophages and contributes to foam cell formation. As such, antioxidants, through their inhibition of LDL oxidation, may contribute to plaque stabilization. Antioxidants may also promote plaque stabilization by reducing matrix degradation withinvulnerable plaque410. Examples of antioxidants include, but are not limited to vitamin E α-tocopherol), vitamin C, and β-carotene supplements. Additionally, HMG CoA reductase inhibitors may also reduce oxidized LDL levels by increasing the total antioxidant capacity of plasma.
• Lipid lowering agents such as statins and antioxidants may be administered at a level of about 0.5 mg/kg per day; higher doses (e.g., 5 times higher) appear to inhibit angiogenesis. See Weis et al.,Statins Have Biphasic Effects on Angiogenesis, Circulation, 105(6):739-745 (Feb. 12, 2000). This dosage level may be achieved by loading a stent with about 10-600 μg of the statin, where the stent is designed to elute the statin over a period of 8 weeks. In one embodiment, the stent may have a length of 13 mm and a diameter of 3 mm. In one embodiment, the stent may have a drug release rate of 150 μg over 10 hours, or 15 μg per hour. In another embodiment, the stent may have a lower release rate of about 20 μg over 10 hours, over 2 μg per hour. Additionally, a compound called “AGI-1067”, developed by AtheroGenics, Inc. of Alpharetta, Ga., may be loaded onto the stent. AGI-1067 has been shown in studies to have direct anti-atherosclerotic effect on coronary blood vessels, consistent with reversing the progression of coronary artery disease.
• In an alternative embodiment, extracellular matrix synthesis promoters may be released fromstent450. Reduced collagen content infibrous cap420 may result from decreased synthesis of extracellular matrix by smooth muscle cells (SMC) and/or increased breakdown by matrix-degrading proteases, thereby leading to thinning and weakening offibrous cap420, predisposingvulnerable plaque410 to rupture with hemodynamic or mechanical stresses.
• Vascular SMC synthesize both collagenous and noncollagenous portions of the extracellular matrix. Lack of sufficient SMC to secrete and organize the matrix in response to mechanical stress could renderfibrous cap420 more vulnerable to weakening by extracellular matrix degradation. Atherosclerosis and arterial injury lead to increased synthesis of many matrix components. In contrast, vulnerable plaque, in general, lacks a sufficient quantity of healthy matrix to provide strength to the fibrous cap to prevent rupture. Thus, promotion of SMC proliferation may lead to plaque stabilization. Delivery of cytokines and growth factors may also achieve SMC proliferation. SMC promoters and proliferative agents such as lysophosphatidic acid may be loaded onto a stent for delivery within a vessel. See Adolfsson et al.,Lysophosphatidic Acid Stimulates Proliferation of Cultured Smooth Muscle Cells from Human BPH Tissue: Sildenafil and Papaverin Generate Inhibition, Prostate, 51(1):50-8 (Apr. 1, 2002). For example, a SMC promoter may be administered at a level of about 0.5 mg/kg per day to higher doses of about 2.5 mg/kg per day. This dosage level may be achieved by loading a stent with about 10-600 μg of the SMC promoter, where the stent is designed to elute the drug over a period of 8 weeks. In one embodiment, the stent may have a drug release rate of 150 μg over 10 hours, or 15 μg per hour. In another embodiment, the stent may have a lower release rate of about 20 μg over 10 hours, over 2 μg per hour.
• In an alternative embodiment, inhibitors of plaque inflammation and extracellular matrix degradation may be released fromstent450. Increased matrix degrading activity associated with enzymes derived from cells such as vascular SMC, macrophages and T lymphocytes is a common finding in vulnerable plaque. Studies suggest that matrix metalloproteinases (MMPs) are involved in matrix degradation. Plaque stabilization could be achieved through inhibition of extracellular matrix degradation by preventing the accumulation of macrophages and T lymphocytes in the vulnerable plaque or by inhibiting the proteolytic enzyme cascade directly. Possible methods to achieve MMP inhibition include increasing the levels of natural inhibitors (TIMPS) either by exogenous administration of recombinant TIMPs or administrating synthetic inhibitors. Synthetic inhibitors of MMPs, including tretracycline-derived antibiotics, anthracyclines and synthetic peptides may also be used. MMP inhibitors may be themselves antioxidants and statins based on preclinical animal data. Studies have shown MMP inhibitors, such as cerivastatin to significantly reduce tissue levels of both total and active MMP-9 in a concentration-dependent manner. See Nagashima et al.,A3-hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitor, Cerivastatin, Supresses Production of Matrix Metalloproteinase-9in Human Abdominal Aortic Aneurysm Wall, J. Vascular Surgery, 36(1);158-63 (July 2002). As with statins as described above, MMP inhibitors may be administered at a level of about 0.5 mg/kg per day to higher doses of about 2.5 mg/kg per day. This dosage level may be achieved by loading a stent with about 10-600 μg of the SMC promoter, where the stent is designed to elute the drug over a period of 8 weeks. In one embodiment, the stent may have a drug release rate of 150 μg over 10 hours, or 15 μg per hour. In another embodiment, the stent may have a lower release rate of about 20 μg over 10 hours, over 2 μg per hour. Additionally, Avasimibe, an ACAT (Acyl-CoA: cholesterol acyltransferase) inhibitor, in the 10 mg/kg range appears to impact MMPs and plaque burden, as well as monocyte adhesion. See Rodriguez and Usher,Anti-atherogenic Effects of the acyl-CoA: Cholesterol Acyltransferase Inhibitor, Avasimibe(CI-1011),in Cultured Primary Human Macrophages, Atherosclerosis, 161(1); 45-54 (March 2002).
• Dosages and concentrations described above are exemplary, and other dosages may be applied such that when delivered over a biologically relevant time at the appropriate release rate, gives a biologically relevant concentration. The biologically relevant time may depend on the biologic target but may range from several hours to several weeks with the most important times being from 1 day to 42 days. Dosages may also be determined by conducting preliminary animal studies and generating a dose response curve. Maximum concentration in the dose response curve could be determined by the solubility of a particular compound or agent in the solution and similarly for coating a stent.
• In yet another alternative embodiment, the active agent may induce collateral artery or vessel growth (i.e., angiogenesis or arteriogenesis) near the vulnerable plaque region such that, in the event of a plaque rupture and subsequent occlusive thrombosis, secondary blood paths may bypass the ruptured region and allow for continued blood flow throughout the artery.FIG. 12 illustrates one embodiment ofarterial section1200 with collateral vessels that have been induced with an active agent.Collateral vessels1250,1251,1252 and1253 provide paths for blood flow to continue througharterial section1200 either temporarily until the occlusion is treated, or permanently to provide greater blood flow. The active agent has been delivered throughdrug delivery stents1240 and1242.Primary artery1230 branches intosections1231,1232, and1233 andarrows1205 indicate the direction of blood flow througharterial section1200.Vulnerable plaque1210 is disposed withinarterial branch1232.Stent1240 induces the growth ofcollateral vessels1250,1251 and1252 aroundvulnerable plaque1210.Collateral vessel1251 starts upstream (near stent1240) fromvulnerable plaque1210 and ends just downstream fromvulnerable plaque1210.Collateral vessel1250 starts upstream fromvulnerable plaque1210 and ends further downstream ofarterial branch1232.Collateral vessel1252 starts upstream fromvulnerable plaque1210 and ends atarterial branch1233.
• Alternatively, collateral vessel growth may be induced from an arterial branch that does not contain a vulnerable plaque.Stent1242 carrying an active agent is disposed withinarterial branch1231 which inducescollateral vessel1253 fromarterial branch1231 tobranch1233. As such,collateral vessel1253 may provide an alternate pathway for continued blood flow in the eventvulnerable plaque1210 ruptures. Although therapeutic or biologically active agents for angiogenesis and arteriogenesis have been described above with respect to drug eluting stents, other types of medical devices may be utilized. In one embodiment, for example, needle catheters may be used to deliver agents to induce angiogenesis and/or arteriogenesis. Needle catheters are described in greater detail below with respect toFIGS. 9-10.
• In one embodiment, therapeutic or biologically active agents may be released to induce arteriogenesis or angiogenesis either downstream, or away from the vulnerable plaque to the myocardium. In the event that an occlusive thrombus occurs from a vulnerable plaque, the myocardium perfused by the affected artery may be salvaged. Representative therapeutic or biologically active agents include, but are not limited to, proteins such as vascular endothelial growth factor (VEGF) in any of its multiple isoforms, fibroblast growth factors, monocyte chemoatractant protein 1 (MCP-1), transforming growth factor alpha (TGF-alpha), transforming growth factor beta (TGF-beta) in any of its multiple isoforms, DEL-1, insulin like growth factors (IGF), placental growth factor (PLGF), hepatocyte growth factor (HGF), prostaglandin E1 (PG-E1), prostaglandin E2 (PG-E2), tumor necrosis factor alpha (TBF-alpha), granulocyte stimulating growth factor (G-CSF), granulocyte macrophage colony-stimulating growth factor (GM-CSF), angiogenin, follistatin, and proliferin, genes encoding these proteins, cells transfected with these genes, pro-angiogenic peptides such as PR39 and PR11, and pro-angiogenic small molecules such as nicotine. In one embodiment, 10-600 μg of one or a mixture of these agents may be loaded onto a stent for delivery within a vessel. These agents may have a release rate for up to eight weeks. In another embodiment, a stent may be loaded with 300 micrograms of an angiogenic agent with a release rate of eight weeks. Alternatively, a dose may be determined by those skilled in the art by conducting preliminary animal studies and generating a dose response curve. Maximum concentration in the dose response curve would be determined by the solubility of the compound in the solution.
• In using drug eluting stents and related technology to deliver the vulnerable plaque treatment agent (e.g.,stent450 ofFIG. 4), the active agent may be dispersed or co-dissolved directly in a solution of a matrix such as ethylene vinyl alcohol, ethylene vinyl acetate, poly(hydroxyvalerate), poly (L-lactic acid), poly(D,L-lactic acid), poly(glycolic acid), poly(lactide-co-glycolide) polycaprolactone, polyanhydride, polydiaxanone, polyorthoester, polyamino acids, poly(trimethylene carbobnate), or other suitable synthetic polymers. The polymer may be coated on a stent using dip coating, spin coating, spray coating or other coating methods known in the art.
• FIGS. 5A-5C illustrate the placement ofdrug delivery stent550 to treat bothocclusive plaque560 andvulnerable plaque510 localized downstream fromocclusive plaque560. In this example,vulnerable plaque510 is located near a branched region ofarterial lumen530. In one embodiment,stent550 is a self-expanding stent, and is disposed neardistal end542 ofcatheter540.Catheter540 is advanced througharterial lumen530 and positioned nearocclusive plaque560.Retractable sheath545 maintainsstent550 in a crimped and collapsed position so thatstent550 may be fit withinarterial lumen530. As illustrated inFIG. 5A, assheath545 retracts,stent550 expands and applies physical pressure toocclusive plaque560. In effect,stent550 widensarterial lumen530 that has been narrowed because ofocclusive plaque560.FIG. 5B illustratesstent550 in a fully expanded position, allowing normal blood flow througharterial lumen530.
• Stent550 may be coated with a drug or biologically active agent that releases from the surface ofstent550 whensheath545 retracts andstent550 becomes exposed to the blood inarterial lumen530. The flow of the blood througharterial lumen530 migrates the agent (as indicated by the arrows570) towardsvulnerable plaque510. The agent targetsvulnerable plaque510. In one embodiment, the agent thickens and/or strengthensfibrous cap520. In doing so, the likelihood offibrous cap520 rupturing is reduced. In another embodiment, the distribution, size or consistency oflipid core515 is altered. A combination of agents may be utilized both to thickenfibrous cap520 and alter the size or consistency oflipid core515 ofvulnerable plaque510 to strengthenfibrous cap520.FIG. 5C illustrates the treatment effects of deployingstent550.Occlusive plaque560 has been treated physically by compressing it against the arterial wall.Vulnerable plaque510 has been treated through strengthening and/or thickeningfibrous cap520 and the favorable alteration of the size or distribution of thelipid core515.
• A vulnerable plaque treatment agent may be delivered independent of treating occlusive atherosclerosis.FIG. 6 illustrates a vulnerable plaque treatment agent delivered in the form of a microcapsule ormicroparticle670. The use ofmicroparticle670 allows for delivery of a treatment agent in a controlled manner to ensure treatment over a desired period of time. Somemicroparticles670 possess the characteristic of being degradable at a designated rate.
• Microparticles670 may also be designed to adhere tovessel wall635 by blending in orcoating microparticles670 with materials that promote adhesion tovessel wall635.Microparticles670 may be rendered bioadhesive by modifying them with bioadhesive materials such as gelatin, hydroxypropyl methylcellulose, polymethacrylate derivatives, sodium carboxymethycellulose, monomeric cyanoacrylate, polyacrylic acid, chitosan, hyaluronic acid, anhydride oligomers, polyycarbophils, water-insoluble metal oxides and hydroxides, including oxides of calcium, iron, copper and zinc.Microparticles670 may be modified by adsorbing the bioadhesive material onmicroparticles670 through ionic interactions, coating the bioadhesive material on the microparticles by dip or spray coating, conjugating the bioadhesive material to thepolymer constituting microparticle670, or blending in the bioadhesive material into the polymer constituting themicroparticles670, before themicroparticles670 are formed.
• The particle size ofmicrocapsules670 may be less than about 10 microns to prevent possible entrapment in the distal capillary bed.Microparticles670 may be delivered intra-arterially near the site ofvulnerable plaque610, and also prophylactically at locations that are proximal and distal to vulnerable plaque610 (not shown). Upon delivery withinfusion catheter640,microparticles670 travel a short distance distally before adhering tovessel wall630 nearvulnerable plaque610. The active agent ofmicroparticles670 is then released over time to thicken and/or strengthenfibrous cap620, alter the size or distribution oflipid core615, or both.Microparticles670 may be delivered withinfusion catheter640 or any other delivery device known in the art. In one embodiment, infusion catheter may be a needle catheter having one or more injection ports to releasemicroparticles670.
• Suitable polymers for the controlled-release microparticles670 include, but are not limited to, poly (L-lactide), poly (D,L-lactide, poly(glycolide), poly lactide-co-glycolide), polycaprolactone, polyanhydride, polydiaxanone, polyorthoesters, polyamino acids, poly (trimethylene carbonate), and combinations thereof. Several methods exist for formingmicroparticles670, including, but not limited to solvent evaporation, coacervation, spray drying, and cryogenic processing.
• In solvent evaporation, the polymer is dissolved in a volatile organic solvent such as methylene chloride. The treatment agent is then added to the polymer solution either as an aqueous solution containing an emulsifying agent such as PVA, or as a solid dispersion, and stirred, homogenized or sonicated to create a primary emulsion of treatment agent in the polymer phase. This emulsion is stirred with an aqueous solution that contains a polymer in the aqueous phase. This emulsion is stirred in excess water, optionally under vacuum to remove the organic solvent and harden the microparticles. The hardened microparticles are collected by filtration or centrifugation and lyophilized.
• The microparticles may also be formed by coacervation. In this method, a primary emulsion of treatment agent in an aqueous phase is formed as in the solvent evaporation method. This emulsion is then stirred with a non-solvent for the polymer, such as silicone oil to extract the organic solvent and form embryonic microparticles of polymer with trapped treatment agent. The non-solvent is then removed by the addition of a volatile second non-solvent such as a heptane, and the microparticles harden. The hardened microparticles are collected by filtration or centrifugation and lyophilized.
• In spray drying, the treatment agent, formulated as lyophilized powder is suspended in a polymer phase consisting of polymer dissolved in a volatile organic solvent such as methylene chloride. The suspension then spray dried to produce polymer microparticles with entrapped treatment agent.
• Microparticles may also be formed by cryogenic processing. In this method, the treatment agent, formulated as lyophilized powder is suspended in a polymer phase consisting of polymer dissolved in a volatile organic solvent such as methylene chloride. The suspension is sprayed into a container containing frozen ethanol overlaid with liquid nitrogen. The system is then warmed to −70° C. to liquefy the ethanol and extract the organic solvent from the microparticles. The hardened microparticles are collected by filtration or centrifugation and lyophilized.
• FIGS. 13A-13B illustrate cross-sectional views of one embodiment of a drug eluting stent that may be used to increase the thickness or strengthen, in a controlled manner, the fibrous cap near a vulnerable plaque. Strengthening of and increasing the thickness of the fibrous cap may redistribute and lower the stresses in the fibrous cap, effectively stabilizing the plaque and preventing its rupture.
• Cross-sectional views1300 include lumen1330 (e.g., an arterial lumen) withlipid core1315 of a vulnerable plaque andfibrous cap1320.Stent1340 having stent struts, for example struts1342,1344, is placed withinlumen1330 nearlipid core1315 andfibrous cap1320. In one embodiment of using a drug eluting stent,stent1340 serves as a vehicle for delivering an appropriate therapeutic or biologically active agent to the site of the vulnerable plaque. Afterstent1340 has been deployed at a desired location, it may cause platelet deposition, fibrosis and neointimal formation in the stented region. This fibromuscular response may cause the originalfibrous cap1320 thickness to increase, thereby lowering the stresses in fibrous cap1320 (as illustrated inFIG. 13B). This additional hyperplasia, combined with originalfibrous cap1320 produced bystent1340 can be thought of as a “neo-cap.”Neo-cap1360, as illustrated inFIG. 13B, has developed near the inner diameter ofstent1340. The controlled release of a drug or biologically active agent fromstent1340 may allow an increase infibrous cap1320 thickness because of the injury sufficient to stabilizelipid core1315, but may minimize or prevent excessive restenosis. The type of biologically active agent, the dosage, release rate and the duration of release may influence the growth of neo-cap1360. Therefore, by controlling these factors the growth of neo-cap1360 may be controlled. After the thickness offibrous cap1320 has been increased andlipid core1315 has been stabilized, the size oflumen1330 may be increased by balloon angioplasty if necessary.
• The biologically active agent used for controllingfibrous cap1320 growth may be delivered using a metal stent platform (e.g., stent1340). The drug may be released through a polymer membrane-matrix system that is deposited on the surface of the stent. Polymers such as EVAL can be used for the membrane-matrix system. Several choices of metals are available for making the stent, including but not limited to, stainless steel, cobalt-chromium alloy and shape-memory alloys such as Nitinol. Depending on the design of the stent and delivery system, it may be possible to direct the biologically active agent to act in specific locations of interest in the vulnerable plaque. For example, biologically active agents which are anti-inflammatory in nature may be optimally delivered into or around the plaque shoulder regions, a site of inflammatory cell accumulation where the lipid core edges meet the normal wall opposite the vulnerable plaque. Conversely, it may be possible to direct the biologically active agent away from specific locations of interest in the vulnerable plaque. For example, biologically active agents which are anti-restenotic, such as Actinomyocin-D, may be directed to act away from the expected regions of high stress infibrous cap1320, which coverlipid core1315 in general. These regions would be the shoulder regions or the portion offibrous cap1320 centered circumferentially alonglipid core1315 edge nearestlumen1330. And finally, it may also be possible to designstent1340 or other types of delivery systems that selectively diffuse a biologically active agent appropriately, by leveraging throughstent1340 design the stress-assisted diffusion properties at the stent-plaque interface in these select regions.
• The biologically active agent may also be delivered using a biodegradable polymeric stent. In this case, after the biologically active agent has eluted from the stent, the stent degrades within a certain period of time leaving behind a stabilized plaque. The polymers available for making the stent include poly-L-lactide, polyglycolic/poly-L-lactic acid (PGLA), Poly-L-latic acid (PLLA), poly-L-lactide, polycaprolactone (PCL), poly-(hydroxybutyrate/hydroxyvalerate) copolymer (PHBV) or shape memory polymers such as a compound of oligo(e-caprolactone) dimethacrylate and n-butylacrylate.
• Examples of therapeutic or biologically active agents include but are not limited to rapamycin, actinomycin D (ActD) and their derivatives, antiproliferative substances, antineoplatic, antinflammatory, antiplatelet, anticoagulant, antifebrin, antithrombin, antimitotic, antibiotic and antioxidant substances. Examples of antineoplastics include taxol (paclitaxel and docetaxel). Examples of antiplatelets, anticoagulants, antifibrins and antithrombins include sodium heparin, low molecular weight heparin, hirudin, IIb/IIIa platelet membrane receptor antagonist and recombinant hirudin. Examples of antimitotic agents include methotrexate, azathioprine, vincristine, vinblastine, fluororacil, adriamycin and mutamycin. Examples of cytostatic or antiproliferative agents include angiopeptin, calcium channel blockers (such as Nifedipine), Lovastatin (an inhibitor of HMG-CoA reductase, a cholestrol lowering drug from Merck). Other therapeutic or biologically active agents which may be utilized include alpha-interferon, genetically engineered epithelial cells and dexamethasone. Dosages comparable to that described above with respect to drug eluting stents may be used.
• Stent Grafts
• In one embodiment, a stent graft may be used for the treatment of vulnerable plaque. The stent graft may have a thin, expandable polytetrafluoroethylene (ePTFE) cylindrical tube affixed to an inner surface of a self-expandable stent. The inner surface of the ePTFE tube may have a layer of endothelial cells. The endothelial cells, when dispersed near the vulnerable plaque region, may promote cell migration to form a fully lined monolayer on the lumen surface. The stent graft may also shield existing vulnerable plaque from the possibility of an acute, thrombotic event. If the plaque ruptures, a cascade of blood-vessel wall interactions occurs, resulting in thrombosis and ultimately partial or total arterial occlusion. Therefore, shielding vulnerable plaque from the vessel lumen would eliminate the possibility of plaque contents being exposed to blood flow in case of rupture. In addition, the stent graft may provide reinforcement to the fibrous cap and reduce any physical stress placed on it due to the size of the lipid core.
• FIG. 7 illustrates another embodiment for treating vulnerable plaque in whichstent graft750 is deployed nearvulnerable plaque710.Stent graft750 has a thin expandable polytetrafluoroethylene (ePTFE)cylindrical tube754 affixed toinner surface751 of self-expandable stent752.Inner surface755 ofePTFE tube754 has a layer ofendothelial cells756. The layer ofendothelial cells756 promotes cell migration that eventually forms a complete monolayer on the surface ofarterial lumen730. As such,stent graft750 shields existingvulnerable plaque710 from an occlusive thrombosis event. Moreover,stent graft750 may provide reinforcement tofibrous cap720 and reduce any increased physical stress placed on it in vivo due tolipid core715 presence or other hemodynamic forces.
• ePTFE tube754 serves as a physical barrier betweenvulnerable plaque710 andarterial lumen730. BecauseePTFE lumen surface755 acts as an arterial equivalent,ePTFE tube754 should remain free from occlusion. In one embodiment, theePTFE tube754 is made anti-thrombotic by surface treatment. The surface ofePTFE tube754 may be made anti-thrombotic for use as a vascular graft by seedingsurface755 withendothelial cells756.Endothelial cells756 seeded within vascular grafts have been shown to promote cell migration that eventually form a fully lined monolayer on a lumen surface.
• Several approaches exist to seedstent graft750 withendothelial cells756. In one embodiment, a pressurized sodding technique may be used in whichePTFE tube754 is expanded to 5 psi using media that contain endothelial cells.Endothelial cells756 are isolated from the canine falciform ligament fat. Endothelial cells may also be isolated from human liposuction fat micro-vessel, umbilical veins, and other comparable sources.
• Stent graft750 may be disposed near a targetvulnerable plaque710 in a manner similar to that of adrug eluting stent450,550 at an occlusive site discussed above (e.g., with respect toFIGS. 4 and 5A-5C).Stent graft750 is disposed near a distal end of a catheter (not shown). The catheter is passed througharterial lumen730 so thatstent graft750 is positioned nearvulnerable plaque710. A retractable sheath (not shown) maintains the stent graft in a crimped position so that the stent graft may be advanced withinarterial lumen730. As illustrated inFIG. 7,stent graft750 expands and applies physical pressure tofibrous cap720 surroundingvulnerable plaque710.FIG. 7 illustratesstent graft750 in a fully expanded position, allowing normal blood flow througharterial lumen730.
• FIGS. 8A-8B illustrate cross-sectional views ofstent graft850 havinginner tube854 lined withendothelial cells856 for treating vulnerable plaque. A self-expandable stent852 is used as structural support to keepstent graft850 secured in place withinarterial lumen730. A self-expandable stent may be advantageous over a balloon expandable stent. A self-expandable stent does not require an internal lumen pressure to expand, and so anyseeded cells856 are kept intact. In contrast, a balloon expandable stent could damagecells856 ofstent graft850 when expanded. The self-expandingstent852 may be made from a shape memory alloy such as NiTi (e.g., Nitinol). In order to provide additional flexibility tostent852, stent links (e.g.,860,861) may be eliminated fromstent852. In an alternative embodiment,stent852 may have a series of shape memory metallic rings (not shown) bonded to the outer surface ofePTFE tubing854.
• Various techniques are available to bondePTFE tube854 tostent852. For example, to bond the ePTFE tube to the metal, a primer is first applied to the metallic portions (e.g.,860,861) ofstent852. These rings are then inserted overePTFE tube854. Silicon adhesive is used to bondmetallic rings860,861 toePTFE tubing854. The stent graft is cured at about 150° C. for approximately 15 minutes. The silicon adhesive seeps through the ePTFE tube matrix and after curing acts as a medium that mechanically fastens the ePTFE tube to the metal. The inner surface of the polymeric tube is then seeded with endothelial cells.
• In addition to the shape memory alloys, stent rings860,861 may also be made from shape memory polymers. Various shape memory polymers with great potential for biomedical applications are currently in the research phase. For example oligo(e-caprolactone) dimethacrylate and n-butyl acrylate are two monomeric compounds that, when combined, generate a family of polymers that exhibit excellent shape memory characteristics. The oligo(e-caprolactone) dimethacrylate furnishes the crystallizable “switching” segment (characteristic of shape memory materials) that determines both the temporary and permanent shape of the polymer. By varying the amount of the comonomer, n-butyl acrylate, in the polymer network, the cross-link density can be adjusted. This allows the mechanical strength and transition temperature of the polymers to be tailored over a wide range. Therefore, the stent incorporating these polymers can be deployed using their shape memory characteristics. Furthermore, other polymers such as polyurethane and ultra high molecular weight polyethylene (UHMWPE) can also be used for tubing used in the stent graft.
• In an alternative embodiment,stent graft850 may also be used as an apparatus for local drug delivery.Stent graft850 may be loaded with anti-restenotic, anti-thrombotic, or other vulnerable plaque treatment agents (e.g., as discussed above with respect toFIGS. 4 and 5A-5C). Furthermore, in yet another alternative embodiment,stent graft850 may be radioactively enhanced or incorporated with a material that generates a magnetic susceptibility artifact ofstent graft850.
• Needle Catheter
• In another embodiment, a vulnerable plaque treatment drug or biologically active agent may be injected through or around a vulnerable plaque region. In one embodiment, a needle catheter may be used to inject the biologically active agent. The needle catheter may be adjusted to penetrate various targets around the vulnerable plaque including, but not limited to: fibrous cap, proteoglycan-rich surface layer, subintimal lipid core, proximal or distal regions of the vulnerable plaque, media containing smooth muscle cells around the lipid core, and the periadventitial space.
• In an alternative embodiment, the needle catheter may include sensing capabilities to determine the depth of penetration of the needle, as well as dial-in needle extension. Furthermore, different angle balloons may be added in order to use case-specific ramp angle to penetrate into the vulnerable plaque region while positioning the needle catheter below the actual occlusion. The needle catheter may be placed proximal or distal to the vulnerable plaque region because studies have shown cell localization, activity, and apoptosis have preferential occurrence in the upstream or downstream parts of vulnerable plaque regions.
• FIG. 9A illustrates a cross-sectional view of one embodiment ofneedle catheter950 that may be used to inject a vulnerable plaque treatment agent intoarterial wall980 nearvulnerable plaque910.Vulnerable plaque910 has developed withinarterial wall980, separated fromarterial lumen930 byfibrous cap920.Distal end941 ofcatheter940 hasinflatable balloon948 with at least oneneedle lumen945 extending fromdistal end941 ofcatheter940 alongproximal end947 ofballoon948.Retractable needle945 extends fromneedle lumen942 and penetratesarterial wall980.Inflated balloon948 securesneedle catheter950 at a target location. Moreover, becauseneedle sheath942 is coupled alongproximal end947 ofballoon948,inflated balloon948 provides a penetration angle forneedle945.Needle catheter950, as illustrated, has twoneedles945,946 extending fromdistal end941 ofcatheter950. Any number of needles may be utilized withneedle catheter950. For example, in an alternative embodiment, the needle catheter may have only one needle for injecting a vulnerable plaque treatment agent.
• As illustrated,needle catheter950targets lipid core915 ofvulnerable plaque910 directly. In one embodiment, a lipid lowering agent may be injected intovulnerable plaque910, or agents which could change lipid core properties could be injected. PEG with an aldehyde/gluteraldehyde mix may be injected intolipid core915 potentially cross-linkingvulnerable plaque910 components to inhibit erosion, rupture, or other forms of destabilization. Other vulnerable plaque treatment agents may be used, including antioxidants, and extracellular matrix synthesis promoters (e.g., as discussed with respect toFIGS. 4 and 5A-5C).
• Needle catheter950 may also be configured to include a feedback sensor (not shown) for mapping the penetration depth ofneedles945,946. The use of a feedback sensor provides the advantage of accurately targeting the injection location. Depending on the type of treatment agent used and treatment desired, the target location for delivering the treatment agent may vary. For example, it may be desirable to inject a drug nearfibrous cap920 or media984 ofarterial wall980. Alternatively, it may be desirable to inject a drug intolipid core915, or adventitia986.
• In use,distal end941 ofneedle catheter950 is inserted into the lumen of a patient and guided to a vulnerable plaque region. As illustrated inFIG. 9A,distal end941 ofneedle catheter950 is positioned near aproximal end912 ofvulnerable plaque910. Alternatively,needle catheter950 may be positioned near adistal end914 ofvulnerable plaque910.Vulnerable plaque910 may be detected using the sensor (not shown) disposed onneedle catheter950. By utilizing a sensor, the injection site for treatingvulnerable plaque910 may be precisely identified.
• FIGS. 10A and 10B illustrate cross sectional views of one embodiment of a needle catheter for injecting a vulnerable plaque treatment drug or biological agent.FIG. 10 illustratesneedle catheter1001 with sensing capabilities having elongatedcatheter body1010 that surroundsneedle lumen1012 andinner lumen1014. Housed withininner lumen1014 arefluid lumen1016 andinner member1018 that also containsguide wire1020,guide wire lumen1022, andultrasonic element lumen1024.Inflatable balloon1026 is coupled toinner lumen1014 and theinner member1018.Proximal end1028 ofballoon1026 is coupled todistal end1030 ofinner lumen1014 anddistal end1032 ofballoon1026 is coupled todistal end1036 ofinner member1018.
• In an alternative embodiment, bothguide wire1022 and retractableultrasonic element1034 may be housed withininner member1014.Elongate body1010 surroundsinner member1014 andneedle lumen1012. Housed withininner lumen1014 areinner member1018 andfluid lumen1016.Inner member1018 surroundsguide wire1022 and retractableultrasonic element1034.Inflatable balloon1026 is coupled toinner lumen1014 andinner member1018.Proximal end1028 ofballoon1026 is coupled todistal end1030 ofinner lumen1014 anddistal end1032 ofballoon1026 is coupled todistal end1036 ofinner member1018.
• Theultrasonic element lumen1024 ofinner member1018 houses retractableultrasonic element1034. The distal end of the ultrasonic element has an ultrasound transducer or transducer array and the proximal end contains the associated co-axial cable that connects to an imaging display system (not shown). Ultrasonic waves generated by the ultrasonic element impinge on the surface of a vulnerable plaque or vulnerable plaque region. The timing/intensity of the ultrasonic waves reflected back to the transducer differentiates between the various anatomic boundaries or structures of the vulnerable plaque region, for example, the various layers of an arterial wall. The waves detected by the transducer are converted to electric signals that travel along the coaxial cable to the imaging system. The electrical signals are processed and eventually arranged as vectors based on the digitized data. In one embodiment, the ultrasound transducer has piezoelectric crystal configured for optimal acoustic output efficiency and energy conversion. In alternative embodiments, the crystal is made of PZT or lead-ceramic materials such as PbTiO₃(lead titanate) or PbZrO₃(lead zirconate).
• As further illustrated inFIGS. 10A-10B,retractable needle1013 is housed inneedle lumen1012 and freely movable therein. The hollow, tubular shapedneedle1013, having an inner diameter within a range of approximately 0.002 inch to 0.010 inch (5.1×10⁻³cm to 25.4×10⁻³cm) and an outer diameter within the range of approximately 0.004 inch to 0.012 inch (10.2×10⁻³cm to 30.5×10⁻³cm), provides a fluid channel that extends fromproximal end1040 todistal end1042 ofneedle1013.Distal end1042 ofneedle1013 has a curved tip. In one embodiment,needle1013 has an angle of curvature of about 30 degrees to 90 degrees. The curvature ofneedle1013 facilitates placement of the needle tip near or within a desired target of a vulnerable plaque region.Needle1013 may be formed from a variety of metals including, but not limited to stainless steel, NiTi (nickel titanium) (e.g., Nitinol) or other comparable semi-rigid materials.
• Proximal end1040 ofneedle1013 is coupled toadapter1050 that couples needle1013 toneedle lock1052 andneedle adjustment knob1054.Needle lock1052 is used to secureneedle1013 in place and prevent further movement ofneedle1013 within an arterial lumen onceneedle1013 is placed in the target position.Needle adjustment knob1054 controls accurate needle extension out of the distal end of the catheter and depth of penetration into the vulnerable plaque region. As such, movement ofneedle adjustment knob1054 moves needle1013 in and out ofneedle lumen1012. Onceneedle1013 has penetrated a target to a desired depth,needle lock1052 enablesneedle1013 to be secured in place thereby preventing any movement ofneedle1013 withinneedle lumen1012.
• Adrug injection port1060 is disposed nearproximal end1062 ofneedle catheter1001.Drug injection port1060 couples needlecatheter1001 with various dispensing devices such as a syringe or fluid pump. Fluids injected intodrug injection port1060 travel throughneedle1013 and are dispensed from the distal tip ofneedle1013.
• FIGS. 9B-9D illustrate embodiments ofneedle catheter950 targeting various regions near a vulnerable plaque for injection of a vulnerable plaque treatment agent. As discussed above,needle catheter950 may have a feedback sensor (e.g.,ultrasonic element1034 ofFIG. 10B) to determine and control a penetration depth forneedles945,946. The sensor provides the advantage of accurately targeting a desired injection site. As such,needle catheter950 may inject a vulnerable plaque stabilizing drug or biologically active agent intofibrous cap920 as illustrated inFIG. 9B, regions within thesubintimal space982 ofarterial wall980 as illustrated inFIG. 9C, or regions distal tovulnerable plaque910 as illustrated inFIG. 9D.
• For example, with respect toFIG. 9B antioxidants such as reactive oxygen scavengers (ROS), vitamin C and E may be injected intofibrous cap920. The oxidant acts as a matrix-ase inhibitor to prevent significant collagen degradation withinfibrous cap920.
• In another embodiment,needle catheter950 may also be used as part of a biological or gene therapy method to treatvulnerable plaque910. For example, upregulators of tissue inhibitors of metalloproteinases (TIMPS) may be injected into adventitia986. TIMPS are expressed by surrounding smooth muscle cells to downregulate MMP production. Alternatively, recombinant TF pathway inhibitors (TFPI) may one day be injected intolipid core915 to inhibit thrombosis due to erosion, rupture or other forms of plaque destabilization.
• In yet another embodiment,needle catheter950 may be used to deliver an agent to induce angiogenesis and/or arteriogenesis as described above with respect toFIG. 12. The therapeutic angiogenesis agents and drugs discussed above may be injected near a treatment site as an alternative to delivery by a drug eluting stent.
• FIGS. 11A-11D illustrate flowcharts describing methods for stabilizing vulnerable plaque. The methods described with respect toFIGS. 11A-11D include detecting vulnerable plaque. Various techniques may be utilized to detect the presence and location of vulnerable plaque. For example, an ultrasound probe (IVUS) or an optical coherence tomography probe (OCT) may be guided through the arteries to scan for vulnerable plaque. Alternatively, magnetic resonance imaging (MRI) devices may be able to detect vulnerable plaque. Near Infrared spectroscopy is another technique for detecting vulnerable plaque. For example, certain wavelengths of light penetrate the arterial wall and produce a specific chemical signature that could correlate to vulnerable plaque composition. Additionally, thermography may also be used to detect vulnerable plaque. Plaques that rupture tend to be inflamed, and data indicates this correlates to a higher temperature compared to non-vulnerable type plaques that do not rupture. As such, a temperature sensitive probe that measures the temperature of arteries could indicate the presence of vulnerable plaque. Alternatively, liquid crystal thermography methods may also be used. For example, a balloon material made of a thermochromic liquid crystal material may be able to optically detect property changes when exposed to increases in temperature. When the balloon contacts a vulnerable plaque, the higher temperature of the vulnerable plaque may be detected by analyzing a beam of light directed towards the suspected vulnerable plaque region and the balloon material in contact therewith. The light may undergo a color change in the balloon material as a result of the higher temperature.
• FIG. 11A describes a method to treat vulnerable plaque downstream from an occlusive plaque. The occlusive plaque may be treated with a stent or balloon catheter. The vulnerable plaque may be treated by altering the lipid core and/or strengthening or thickening the fibrous cap surrounding the vulnerable plaque. The vulnerable plaque is first detected by any one of the techniques described above, including but not limited to IVUS, OCT, MRI, near infrared spectroscopy, thermography, and liquid crystal thermography. The vulnerable plaque may be downstream from an occlusive plaque that has been detected, for example, with an angiogram. A drug delivery catheter is provided having a vulnerable plaque stabilizing agent. In one embodiment, the drug delivery catheter may deploy a drug eluting stent. The drug eluting stent is positioned at the occlusive plaque to widen the arterial lumen whose blood flow has been impeded by the plaque. The vulnerable plaque stabilizing agent is released towards a vulnerable plaque region located downstream from the release site. Alternatively, the agents may be in the form of microparticles to control the release of the agents over time. The agents released from the drug delivery catheter may include lipid lowering agents, antioxidants, extracellular matrix synthesis promoters, or inhibitors of plaque inflammation and extracellular degradation.
• FIG. 1B describes a method to treat vulnerable plaque by inducing collateral artery or vessel growth to the myocardium downstream from or adjacent to an occlusive plaque. The occlusive plaque may be treated with a stent or balloon catheter. By inducing therapeutic angiogenesis (e.g., collateral artery or vessel growth), blood flow is maintained in case a vulnerable plaque ruptures leading to an occlusive thrombosis. The vulnerable plaque is first detected by any one of the techniques described above, including but not limited to IVUS, OCT, MRI, near infrared spectroscopy, thermography, and liquid crystal thermography. The vulnerable plaque may be downstream from an occlusive plaque that has been detected, for example, with an angiogram.
• A drug delivery catheter or stent is provided having an agent that induces collateral artery or vessel growth. In one embodiment, the drug delivery catheter may deploy a drug eluting stent. The drug eluting stent is positioned at the occlusive plaque to widen the arterial lumen whose blood flow has been impeded by the plaque. The agent to induce collateral artery or vessel growth is released towards a vulnerable plaque region located downstream from the drug release site. Representative therapeutic or biologically active agents include, but are not limited to, proteins such as vascular endothelial growth factor (VEGF) in any of its multiple isoforms, fibroblast growth factors, monocyte chemoatractant protein 1 (MCP-1), transforming growth factor alpha (TGF-alpha), transforming growth factor beta (TGF-beta) in any of its multiple isoforms, DEL-1, insulin like growth factors (IGF), placental growth factor (PLGF), hepatocyte growth factor (HGF), prostaglandin E1 (PG-E1), prostaglandin E2 (PG-E2), tumor necrosis factor alpha (TBF-alpha), granulocyte stimulating growth factor (G-CSF), granulocyte macrophage colony-stimulating growth factor (GM-CSF), angiogenin, follistatin, and proliferin, genes encoding these proteins, cells transfected with these genes, pro-angiogenic peptides such as PR39 and PR11, and pro-angiogenic small molecules such as nicotine.
• FIG. 11C describes a method to treat vulnerable plaque by implanting a stent graft on the arterial wall near a vulnerable plaque. This method of vulnerable plaque stabilization may be performed independent of treating an occlusive plaque. The vulnerable plaque is first detected by any one of the techniques described above, including but not limited to IVUS, OCT, MRI, near infrared spectroscopy, thermography, and liquid crystal thermography. The stent graft is disposed near a distal end of a catheter and advanced within the arterial lumen and positioned near a vulnerable plaque. Retracting a sheath covering the stent graft deploys the stent graft. In one embodiment, the stent graft has a thin ePTFE cylindrical tube affixed to the inner surface of a self-expandable stent. The inner surface of the stent has a layer of endothelial cells. The layer of endothelial cells promote cell migration that forms a fully lined monolayer on the arterial lumen surface. As such, the stent graft shields existing vulnerable plaque from an occlusive thrombotic event. Moreover, the stent graft provides reinforcement to the fibrous cap and reduces any physical stress placed on it due to the presence of the lipid core and hemodynamic forces.
• FIG. 11D describes another method to treat vulnerable plaque. The vulnerable plaque may be treated by injecting a stabilizing drug or biologically active agent at various locations within and around the vulnerable plaque. The vulnerable plaque is first detected by any one of the techniques described above, including but not limited to IVUS, OCT, MRI, near infrared spectroscopy, thermography, and liquid crystal thermography. A needle catheter is advanced through an arterial lumen and positioned near a proximal end of the vulnerable plaque. Alternatively, the needle catheter may be positioned at or near a distal end of the vulnerable plaque. A sensor disposed on the needle catheter determines a penetration depth for the needle catheter. The needle catheter may be adjusted to penetrate various targets around the vulnerable plaque including, but not limited to: fibrous cap, proteoglycan-rich surface layer, subintimal lipid core, proximal or distal regions of the vulnerable plaque, media containing smooth muscle cells above the lipid core and the adventitial space. The agents released from the drug delivery catheter may include lipid lowering agents, antioxidants, extracellular matrix synthesis promoters, inhibitors of plaque inflammation and extracellular degradation.
• In the foregoing specification, the invention has been described with reference to specific exemplary embodiments thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention as set forth in the appended claims. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense.

Claims (41)

1. An apparatus, comprising:

an elongated catheter body adapted for insertion in a body lumen; and

a drug delivery device coupled near a distal portion of said elongated body, said drug delivery device configured to deliver a biologically active agent to stabilize a vulnerable plaque.

2. The apparatus ofclaim 1, wherein said drug delivery device comprises:

a balloon disposed at a distal end of said drug delivery device; and

at least one needle housed within said drug delivery device, wherein said at least one needle is moveable from a retracted position to an extended position, and wherein an angle of needle penetration relative to said elongated catheter body corresponds to an inflation of said balloon.

3. The apparatus ofclaim 2, further comprising a sensor near said distal portion of said catheter, wherein said sensor determines a penetration depth of said at least one needle.

4. The apparatus ofclaim 1, wherein said biologically active agent comprises lipid lowering agents.

5. The apparatus ofclaim 1, wherein said biologically active agent comprises antioxidants.

6. The apparatus ofclaim 1, wherein said biologically active agent comprises anti-inflammatory agents.

7. The apparatus ofclaim 1, wherein said biologically active agent comprises extracellular matrix synthesis promoters.

8. The apparatus ofclaim 1, wherein said drug delivery device delivers up to 600 μg of said biologically active agent.

9. A method for stabilizing a vulnerable plaque in a lumen wall, comprising:

detecting said vulnerable plaque;

advancing a needle catheter near said vulnerable plaque; and

delivering a vulnerable plaque stabilizing agent with said needle catheter near said vulnerable plaque.

10. The method ofclaim 9, further comprising determining a penetration depth of said needle catheter.

11. (canceled)

12. The method ofclaim 9, wherein delivering said vulnerable plaque stabilizing drug comprises targeting an intimal layer near said vulnerable plaque.

13. The method ofclaim 9, wherein delivering said vulnerable plaque stabilizing drug comprises targeting an adventitial layer near said vulnerable plaque.

14. The method ofclaim 9, wherein delivering said vulnerable plaque stabilizing drug comprises targeting a media layer near said vulnerable plaque.

15. The method ofclaim 9, wherein delivering said vulnerable plaque stabilizing drug comprises targeting said lipid core of said vulnerable plaque region.

16. The method ofclaim 15, wherein targeting said lipid core comprises delivering a cross-linking agent.

17. A method ofclaim 15, wherein targeting said lipid core comprises delivering a matrix-ase inhibitor.

18. The method ofclaim 13, wherein targeting said adventitial layer comprises delivering a collagen synthesis promoter.

19. The method ofclaim 13, wherein targeting said adventitial layer comprises gene therapy.

20. The method ofclaim 13, wherein targeting said adventitial layer comprises inserting said needle into said body lumen wall at a point proximal to said vulnerable plaque region, and extending said needle to said adventitial layer.

21. The method ofclaim 14, wherein targeting said media layer comprises inserting said needle into said body lumen wall at a point proximal to said vulnerable plaque region, and extending said needle to said media layer.

22. (canceled)

23. The method ofclaim 15, wherein targeting said lipid core comprises inserting said needle into said body lumen wall at a point proximal to said lipid core, and extending said needle to said lipid core.

24. The method ofclaim 9, wherein said vulnerable plaque stabilizing agent strengthens said fibrous cap.

25. The method ofclaim 9, wherein said vulnerable plaque stabilizing agent reduces a size of a lipid core of said vulnerable plaque.

26. The method ofclaim 9, wherein said vulnerable plaque stabilizing agent thickens said fibrous cap.

27. A method for treating a vulnerable plaque, comprising:

advancing a medical device within a body lumen; and

delivering a biologically active agent from said medical device, wherein said biologically active agent induces a therapeutic angiogensesis growth away from said vulnerable plaque to maintain a blood perfusion in the event of an occlusive thrombosis from a rupturing of said vulnerable plaque.

28. The method ofclaim 27, wherein delivering comprises releasing said biologically active agent upstream from said vulnerable plaque.

29. A method ofclaim 28, further comprising providing a drug delivery catheter to release said biologically active agent.

30. The methodclaim 27, wherein delivering comprises releasing said biologically active agent through a bloodstream near said vulnerable plaque.

31. The methodclaim 27, wherein delivering comprises releasing said biologically active agent towards a lumen wall near said vulnerable plaque.

32. The methodclaim 27, wherein delivering comprises sustained-releasing said biologically active agent.

33. The method ofclaim 32, wherein sustained-releasing said biologically active agent comprises releasing said biologically active agent over a period up to about 6 months.

34. The method ofclaim 29, wherein said drug delivery catheter comprises dip coating a drug eluting stent with said biologically active agent.

35. The method ofclaim 29, wherein said drug delivery catheter comprises spin coating a drug eluting stent with said biologically active agent.

36. The method ofclaim 31, wherein releasing said biologically active agent towards said lumen wall comprises adhering a plurality of micro-particles to said lumen wall.

37. The method ofclaim 27, wherein said biologically active agent is selected from a group consisting of vascular endothelial growth factor (VEGF), fibroblast growth factors, monocyte chemoatractant protein 1 (MCP-1), transforming growth factor alpha (TGF-alpha), transforming growth factor beta (TGF-beta, DEL-1, insulin like growth factors (IGF), placental growth factor (PLGF), hepatocyte growth factor (HGF), prostaglandin E1 (PG-E1), prostaglandin E2 (PG-E2), tumor necrosis factor alpha (TBF-alpha), granulocyte stimulating growth factor (G-CSF), granulocyte macrophage colony-stimulating growth factor (GM-CSF), angiogenin, follistatin, proliferin, pro-angiogenic peptides, and pro-angiogenic small molecules.

38. The method ofclaim 27, wherein delivering said biologically active agent induces a therapeutic angiogenesis growth to a myocardium.

39. The method ofclaim 27, wherein delivering said biologically active agent comprises delivering up to 600 μg of said biologically active agent.

40. An apparatus for stabilizing a vulnerable plaque in a lumen wall, comprising:

means for detecting said vulnerable plaque;

means for advancing a needle catheter near said vulnerable plaque; and

means for delivering a vulnerable plaque stabilizing agent with said needle catheter near said vulnerable plaque, wherein said vulnerable plaque stabilizing agent increases a thickness of a fibrous cap.

41. An apparatus for treating a vulnerable plaque, comprising:

means for advancing a medical device within a body lumen; and

means for delivering a biologically active agent from said medical device, wherein said biologically active agent induces a therapeutic angiogenesis growth away from said vulnerable plaque to maintain a blood perfusion in the event of an occlusive thrombosis from a rupturing of said vulnerable plaque.

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